The skin represents the body's initial line of defense against the environment. The body is continually exposed to a barrage of molecules, many of which can cause an adverse reaction upon contact. These reactions can follow a spectrum from causing a dramatic and detrimental effect on an individual to skin discoloration and blotching.
The reactions include typical allergic dermatitis, including contact dermatitis and atopic dermatitis, as well as irritant dermatitis.
Contact dermatitis is an inflammation of the skin, which occurs when the skin comes in contact with substances that the skin is sensitive or allergic to. The reaction usually appears within 24-48 hours after exposure to the allergen. Common symptoms include redness, itching and swelling. Sometimes blistering and weeping of the skin also develop. The clinical symptoms of contact dermatitis can include acute eczema accompanied by erythema, edema, papula, vesicle, erosion, and itching. Repeated exposure to an irritant can lead to the development of eczema accompanying lichenification and infiltration. Allergic contact dermatitis can appear after initial or prolonged exposure to an irritant. Contact dermatitis includes irritant dermatitis, phototoxic dermatitis, allergic dermatitis, photoallergic dermatitis, contact urticaria, systemic contact-type dermatitis and the like.
A wide range of agents can cause allergic contact dermatitis including for example, metals (e.g. nickel, chromium, cobalt), fragrances, chemicals, cosmetics, textiles, pesticides, plastics, and pollen (see, for example, R. J. G. Rycroft et al. “Textbook of Contact Dermatitis”).
Therapeutic agents such as drugs may also cause allergic contact dermatitis, particularly when administered transdermally. It is well known that many drugs, e.g., topical ointments, including some currently marketed in the United States (e.g. clonidine) sensitize the skin when used.
Skin sensitization may be produced not only by transdermally delivered drugs, but also by a non-sensitizing drug combined with skin sensitizing permeation enhancers, or a combination of a sensitizing drug and a sensitizing permeation enhancer. Penetration of these sensitizing agents into the skin and the resulting adverse reaction of the skin may persist well beyond the time that the transdermal patch is removed from the skin. The reaction of the skin may be a source of discomfort and a clinical complication in patients suffering from such a reaction.
Atopic dermatitis is developed by exposure to various antigens, since an individual has an atopic disposition which is hypersensitivity against a certain substance. The clinical symptoms include marked itching, skin hypertrophy, infiltration, lichenification and the like.
Irritant dermatitis can occur when too much of a substance is used on the skin or when the skin is sensitive to a certain substance. Susceptibility can include a genetic component. Skin-irritating agents are substances (e.g. soap) that cause an immediate and generally localized adverse response. The response is typically in the form of redness and/or inflammation and generally does not extend beyond the immediate area of contact. Symptoms that are commonly seen include redness, scaling, and the skin looking irritated and sore.
Psoriasis is a skin condition associated with hyper-proliferation of skin cells and immunologic involvement. Psoriasis is a common, idiopathic chronic skin disease characterized by inflamed, scaling, skin lesions containing infiltrates of neutrophils, lymphocytes, and monocytes. Psoriasis manifests in many forms, including cutaneous, mucosal, ungual, and even psoriatic rheumatism. The most effective treatment in the control of localized psoriasis for most patients is the use of topical corticosteroids and topical coal-tar preparations. With certain patients who have generalized psoriasis, it has been necessary to use a variety of systemic chemotherapeutic agents, especially methotrexate.
Certain irritants may cause both allergic and non-allergic contact dermatitis. For example, latex. Latex refers to a type of plastic made from the milky sap of the rubber tree, and contains many proteins which can cause allergic reactions in sensitive individuals. Symptoms can range from watery eyes, hives, rash, swelling, wheezing and in severe cases, anaphylaxis. These responses can occur when latex items touch the skin; the mucous membranes (including the mouth, bladder, genitals, or rectum), and open wounds or bloodstream (especially during surgery). Anybody can develop latex sensitivity. People at increased risk for developing latex allergy include workers with ongoing latex contact (like health care workers), persons with many environmental allergies (hay fever), and those with spina bifida. Latex is found in a wide array of common products, including, for example: gloves, balloons, band-aids, tourniquets, bandages, catheters, rubber bands, IV, other tubing (ex. stethoscopes), art supplies, pacifiers, bottle nipples, diapers, condoms/diaphragms, elastic, chewing gum, carpeting, hand grips of bicycles and motorcycles, shoe soles, auto tires, swimming goggles and equipment.
The more common reaction to latex products is not allergic, but rather, irritant contact dermatitis, which can cause dry, itchy, irritated areas on the skin, usually the hands. Skin reactions include a rash that usually begins 24 to 48 hours after contact. It may progress to oozing blisters or spread away from area touched by latex. Latex allergy (immediate hypersensitivity) is a more serious reaction. Certain proteins in latex cause an allergic reaction. The amount of exposure needed to cause symptoms is not known. Very low levels of exposure can trigger allergic reactions in some people, while having no affect to most people. Reactions usually begin within minutes of exposure to latex, but can occur hours later and have a variety of symptoms. Mild reactions to latex usually cause skin redness, hives, or itching. More severe reactions can cause respiratory or breathing symptoms such as runny nose, sneezing, itchy eyes, scratchy throat, and asthma (trouble breathing, coughing, and wheezing).
Individuals can also develop allergic dermatitis and/or irritant dermatitis in response to insects and plants and shrubbery. For example, certain plants such as poison ivy excrete chemicals that upon contact can cause adverse reactions in humans. These reactions may particularly occur during gardening or nature walks.
Many animals can also suffer from a variety of skin irritations and inflammations generally known as dermatitis. For example, all animals can develop contact dermatitis caused by flea, mosquito, or other insect bites, allergies, external stimulation such as from prickly plants, and for other reasons. The condition has been notoriously difficult to treat. Veterinarians occasionally resort to injections of various medicines in an attempt to alleviate the symptoms and cure the dermatitis.
Presently known therapies for treating or preventing reactions associated with such irritants are inadequate. For example, steroidal agents and antihistamine agents have been used as therapeutic agents for contact dermatitis, and these and a part of the so-called anti-allergic agents have been used for atopic dermatitis. The most widely prescribed drugs to treat dermatologic disease are corticosteroids, also known as glucocorticosteroids or glucocorticoids. Approximately 50% of prescriptions written by dermatologists are for topical corticosteroids. However, these drugs can cause adverse reactions and/or are not fully effective. Systemic corticosteroids are often required in some severe dermatologic diseases but topical treatment is preferred in most responsive cases because it causes fewer systemic adverse effects.
Individual topical corticosteroid preparations vary in anti-inflammatory potency and clinical efficacy.
Though some steroids, particularly mid- to high-potency steroids, are efficacious in chronic dermatoses, long term use of steroids is associated with serious local side effects. These include skin atrophy (thinning, telangiectasia, striae) and a prompt rebound flare when the steroid is stopped. Treatment of large areas of skin and use of occlusive dressings can also increase the potential for adverse effects. This is especially the case in children.
Examples of anti-histamine agents include diphenhydramine hydrochloride, mequitazine, promethazine hydrochloride, and chlorpheniramine maleate anti-histamines have been used mainly to reduce itchiness. Anti-allergic agents include tranilast, ketotifen fumarate, oxatomide, and azelastine hydrochloride. In general, conventional so-called antiallergic agents are either ineffective or fail to show satisfactory therapeutic effects on contact dermatitis and atopic dermatitis.
Accordingly, there is a need for a treatment for skin reactions including allergic dermatitis (contact dermatitis and atopic dermatitis), as well as irritant dermatitis.
The pathophysiologic mechanisms involved in the above-described skin disorders and the evolution of such inflammatory processes are poorly understood. There are numerous skin conditions characterized by increased T cell activation and abnormal antigen presentation in the dermis and epidermis. Thus, there has been speculation that skin cells are important in the generation of a cutaneous inflammatory response (Kupper, “Immune and Inflammatory Processes in Cutaneous Tissues”, J. Clin. Invest., 86, pp. 1783-89 (1990)).
CD1d-restricted NK T cells are among the immune system cells found in the skin. The in vivo functions of CD1d-restricted NK T cells are not fully known. They are involved in the IgG response to GPI-anchored proteins of various parasites, contribute to the IL-12-mediated rejection of tumors, and appear to regulate some autoimmune disorders and clearance of certain infections through the production of cytokines. Many of these functions have been observed by using lipid ligands that bind CD1d and activate NK T cells. For example, α-gal-cer.
In humans, the direct cellular targets for their immunomodulatory function(s) have remained enigmatic.